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To the Editor:—
I read with great interest the recently published article by Nakahata et al.
,1 “Propofol Restores Brain Microvascular Function Impaired by High Glucose via
the Decrease in Oxidative Stress.” In this study, the authors observed that propofol, at potentially clinically relevant concentrations, dose-dependently attenuated or abolished rat brain microvascular dysfunction induced by high glucose, and that the protection of propofol, similar to that of the superoxide dismutase mimetic Tempol, is attributable to its inhibition of superoxide production induced by high glucose. Further, the authors found that nicotinamide adenine dinucleotide phosphate oxidase, but not xanthine oxidase, is the major source of superoxide production in the brain microvascular arteriolar wall after high glucose stimulation.1 This is an interesting finding because nicotinamide adenine dinucleotide phosphate oxidase has also be reported as a major source of superoxide production in the diabetic heart2 that is complicated by hypertrophic cardiomyopathy in the rat.3 Therefore, theoretically, propofol may provide protection against oxidative injury of the diabetic heart through superoxide scavenging.

I congratulate Nakahata et al.
for the interesting and detailed results about the role of superoxide scavenging in propofol restoration of microvascular function impaired by high glucose.

However, I think that the study design of Nakahata et al.1 should be debated. Oxidative stress results from an imbalance between the formation and neutralization of pro-oxidants (such as superoxide and hydrogen peroxide). Pathologic processes (such as high glucose or diabetes) disrupt this balance by increasing the formation of prooxidant in proportion to the available antioxidants (such as the intracellular antioxidant enzymes: superoxide dismutase and glutathione peroxidase) and subsequently result in oxidative injury (oxidative stress). Therefore, a more suitable title for the study of Nakahata et al.1 would be “Propofol Restores Brain Microvascular Function Impaired by High Glucose via
the Decrease in Superoxide Production,” given that parameters that reflect oxidative damages were not measured in the study.

High glucose has been shown to decrease intracellular levels of glutathione,4 a potent endogenous antioxidant that converts hydrogen peroxide (H2O2) to water (H2O) catalyzed by glutathione peroxidase (i.e.
, 2GSH + H2O2→ GSSG + 2H2O, where GSSG represents glutathione disulfide). Acute high glucose5 as well as chronic hyperglycemia6 can significantly increase the production of tumor necrosis factor (TNF)-α in humans. TNF-α in turn has been shown to cause significant human vascular endothelial cell apoptotic death, accompanied by more profound decreases in intracellular glutathione peroxidase activity (approximately 50% reduction vs.
control) than in superoxide dismutase activity (approximately 30% reduction vs.
control).7 As such, a small dose of hydrogen peroxide can significantly augment TNF-α cellular toxicity, which can be attenuated by treatment with propofol.7 Propofol has been shown to attenuate hydrogen peroxide–induced myocardial dysfunction in rats.8 Of interest, we recently found that TNF-α (at 40 ng/ml) caused more profound increases in intracellular hydrogen peroxide (approximately 20-fold) than in superoxide (approximately 16-fold) in cultured human umbilical vein endothelial cells as measured by dihydroethidium and dichlorofluorescein fluorescence straining, respectively, and that abolishment of the increase of hydrogen peroxide but not the superoxide overproduction prevented TNF-α cellular toxicity (Fang Wang, M.D., M.Sc., Zhengyuan Xia, M.D., Ph.D., Jingping Quyang, M.D., Wuhan, Hubei, China, unpublished observation, April 2007).

I am surprised that hydrogen peroxide production was not measured in the study of Nakahata et al.1 Furthermore, I propose that attenuation of hydrogen peroxide–mediated oxidative injury could be the major mechanism by which propofol restores brain microvascular function impaired by high glucose.